Abstract 5102: Identifying targets for melanoma therapy: Biological and clinical implications of BRAF L597 mutants

Recurrent driver mutations in BRAF (V600), NRAS (G12/13, Q61), KIT (W557, V559, L576, K642, D816), GNAQ (Q209) and GNA11 (Q209) have previously been identified in malignant melanomas, but over one-third of cases have no known potentially actionable targets. To identify novel drivers, we performed whole-genome sequencing of a tumor-normal pair from a patient with an aggressive, chemotherapy-naïve metastatic melanoma which was pan-negative for the mutations listed above. Our data analysis pipeline revealed the landscape of somatic single nucleotide polymorphisms (SNPs), insertions and deletions, copy number variations, and structural variants. A subset of the nonsynonymous SNPs was validated by direct sequencing, resulting in the identification of a somatic BRAF L597R mutation. Surrogate kinase assays suggest that this mutant is sensitive to both BRAF and MEK inhibitors. Subsequent mutational analyses showed that BRAF L597 mutations were in 2 of 34 (6%) ‘pan-negative’ tumors. Collectively, these data demonstrate the frequency and potential therapeutic implications of BRAF L597 mutations in melanoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5102. doi:1538-7445.AM2012-5102